The present invention relates to biodegradable block polymers, and more specifically, loaded micelles thereof formed with biologically active materials, for use in drug delivery.
The majority of clinically used drugs are low molecular weight polymer compounds (<500 daltons) that exhibit a short half-life in the blood stream and high clearance rates. These small molecules diffuse rapidly through the body in both healthy and diseased tissue often causing serious side effects. Moreover these therapeutic agents have limited solubility and stability and they are often toxic, making efficient drug delivery systems to overcome these transport problems of critical interest. Polymer therapeutics (including polymeric drugs, polymeric-drug conjugates, polymer-protein conjugates, polymer-DNA conjugates and polymeric micelles to which drugs are covalently bound or physically incorporated) is an ongoing area of research.
The most widely studied delivery agents are supramolecular structures generated from block copolymers where one block is selectively solvated in water. These micelles form core-shell or compartmentalized morphologies capable of sequestering hydrophobic cargos, and are typically several tens of nanometers in diameter with a relatively narrow size distribution. The major obstacle for supramolecular drug-delivery systems based on a non-covalent entrapment of drugs into core-shell architectures is the lack of stability of polymer micelles at high dilution and low drug loading levels. Improvement in stability has been achieved by cross-linking the core or shell of premixed micelles, or by structural designs promoting non-covalent interactions between blocks, including, for example, polyelectrolyte complexation between oppositely charged block ionomers, stereocomplexation, or hydrogen bonding. Despite the improved stability from the chemical cross-linking, this approach may not be optimal for the encapsulation of a guest molecule, or for biodegradability.
In addition, non-covalent interactions can also be used to enhance carrier-cargo complexes to improve loading levels and mitigate cargo release kinetics. For example, interaction between an ammonium ion and a carboxylate anion with the formation of an ion-pair complex is an important type of molecular recognition process. This acid-base motif has been exploited for supramolecular assembly of gels, controlling diblock copolymer self-assembly to form domain patterns, small molecule mixtures, interfaces, surfactant/polymer/dendrimer supramolecular complexes, liquid crystal/polymer complexes, thermally responsive gels, etc. Specific acid-base interaction between hydrophobic drug molecules (R1—COOH) and polymer segments (NH2—R2) improved the drug loading capacity of block copolymer micelles in aqueous media. Similarly, core/shell micelles with acid functionalities in the core sequestered high loading levels of DOX, but unfortunately DOX molecules had to be chemically linked to the core through the acid groups, which did not show biological activity in cancer treatment. Similarly, the use of another non-covalent interaction, stereocomplexation, has been used to significantly bolster drug loadings as well as to control the release rates.
Micelle stability in ultradilute conditions and enhanced cargo-carrier loading levels remain important challenges for drug delivery systems.